Dramatic effect of solvent hydrogen bond basicity on the regiochemistry of SNAr reactions of electron-deficient polyfluoroarenes

Article abstract of DOI:10.1021/ol902353t

[Chemical Equation Presented] It was found that solvent hydrogen bond basicity (SHBB) significantly affects the regiochemistry of the S_NAr reaction between secondary amines and activated polyfluoroarenes. A plausible mechanism involving a six-m

Full text of DOI:10.1021/ol902353t

ORGANIC
LETTERS
2009
Vol. 11, No. 24
5662-5664
Dramatic Effect of Solvent Hydrogen
Bond Basicity on the Regiochemistry of
SNAr Reactions of Electron-Deficient
Polyfluoroarenes
Xiaolun Wang,* Edward J. Salaski, Dan M. Berger, and Dennis Powell
Chemical Sciences, Wyeth Research, 401 North Middletown Road,
Pearl RiVer, New York 10965
wangx4@wyeth.com
Received October 12, 2009
ABSTRACT
It was found that solvent hydrogen bond basicity (SHBB) significantly affects the regiochemistry of the SNAr reaction between secondary
amines and activated polyfluoroarenes. A plausible mechanism involving a six-membered transition state is invoked for the formation of an
ortho-substituted isomer, which is likely organized by a hydrogen bond. Evidence for this hypothesis is presented, and a regioselective
amination reaction of activated polyfluoroarenes has been developed.
Hydrogen bonding interactions can play a determining role
in organic synthesis, as exemplified by the recent develop-
ment of chiral hydrogen bond donors in asymmetric orga-
nocatalysis.1 Additionally, solvents have long been recog-
nized as one of the most common variables for reaction
optimization.2 While discussions about solvent effects are
frequently included in synthetically oriented publications, to
the best of our knowledge, the concept of solvent hydrogen
bond basicity (SHBB), well-known in the field of physical
organic chemistry,3 has not been reported in a synthetic
application. In this communication, we report a dramatic
effect of SHBB on the regiochemistry of SNAr reactions
involving electron-deficient polyfluoroarenes, leading to the
discovery of a regioselective synthesis of aminofluoroarenes.
In a program to prepare inhibitors of B-Raf kinase as cancer
therapeutics,4 it was found that the SNAr reaction5 (eq 1), under
typical conditions,6 of 2,4-difluoroacetophenone (1) with (1S,4S)-
tert-butyl-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (2) gave
a mixture of regioisomers only slightly favoring the desired
(3) (a) Laurence, C.; Berthelot, M. Perspect. Drug DiscoVery Des. 2000,
18, 39–60. (b) Taft, R. W.; Gurka, D.; Joris, L.; Schleyer, P. R.; Rakshys,
J. W. J. Am. Chem. Soc. 1969, 91, 4801–4808. (c) Laurence, C.; Brameld,
K. A.; Graton, J.; Le Questel, J.-Y.; Renault, E. J. Med. Chem. 2009, 52,
4073–4086. (d) Kamlet, M. J.; Taft, R. W. J. Am. Chem. Soc. 1976, 98,
377. (e) Besseau, F.; Laurence, C.; Berthelot, M. Bull. Soc. Chim. Fr. 1996,
133, 381–387. (f) Le Questel, J.-Y.; Laurence, C.; Lachkar, A.; Helbert,
M; Berthelot, M. J. Chem. Soc., Perkin Trans. 2 1992, 2091–2094.
(1) Doyle, A. G.; Jacobsen, E. N. Chem. ReV. 2007, 107, 5713–5743.
(2) Reichardt, C. SolVents and SolVent Effects in Organic Chemistry;
VCH: Weinheim, 2003; pp 147-328 and 472-475.
10.1021/ol902353t  2009 American Chemical Society
Published on Web 11/13/2009

1,a
Table 1. Solvent Effect on the Regioselectivity of Reaction
d
solvent
3a:3bb
εrc
pKHB
toluene
dioxane
MeCN
pyridine
DMF
<2:98
<2:98
12:88
33:67
60:40
67:33
81:19
94:6
2.38
2.21
-0.363e
1.033a
0.913a
1.863a
2.103f
2.793f
2.583a
3.563a
35.94
12.91
36.71
36.12
46.45
28.30
DMPUe
DMSO
HMPA
a Reaction conditions: 0.05 mmol of 2, 1.2 equiv of 1, 3.0 equiv of
K2CO3, 1 mL of solvent, 70 °C, 24 h. b Determinated by 1H NMR. c Relative
dielectric constant.2 d A scale for hydrogen bond basicity.3 e 1,3-Dimethyl-3,4,5,
6-tetrahydro-2(1H)-pyrimidinone.
Figure 1
hydrogen bond basicity.
. Relationship of the regioselectivity of reaction 1 to solvent
para-isomer 3a despite the steric hindrance for the ortho-isomer
3b. As the separation of these isomers was nontrivial on the
targeted scale, we began a systematic effort to optimize the
regioselectivity of this reaction.
Scheme 1. Plausible Mechanism for the Formation of
1
Regioisomers in the SNAr Reaction
Screening7 of alternative bases and the addition of catalysts
such as DMAP did not yield any improvement in selectivity;
however, a breakthrough came during an extensive solvent
survey (Table 1). It was found that hexamethylphosphoramide
(HMPA) is superior to other solvents, providing a 94:6 mixture
of 3a and 3b. Although the para product appeared to be
preferred in more polar solvents, acetonitrile gave mainly the
ortho product. A careful analysis of the relationship between
the ortho/para isomer ratios and SHBB revealed that solvents
with high hydrogen basicity tend to give more para-substituted
product (Figure 1). The pKHB parameter, which was first
introduced by Taft,3b can be used as a measurement of SHBB.
From acetonitrile to HMPA, the regioselectivity jumps from
12:88 to 94:6 in line with the pKHB increase from 0.91 to 3.56.
Other polar solvents examined, having pKHB between these two,
gave intermediate regioselectivities. The dielectric constants of
all these solvents are relatively similar.
nucleophile amine and nitro group in the transition state of
the SNAr reaction of ortho-chloronitrobenzene through either
hydrogen bonding10 or electrostatic attraction. In our system,
built-in solvation may also play an important role in the
formation of the ortho-isomer. In Pathway A, amine 2 attacks
the para position to yield a zwitterionic intermediate INT-A
via a partially charged transition state TS-A, consistent with
the observation that solvents with high dielectric constants
give more of the para-isomer. In Pathway B, leading to ortho
isomer 3b, a neutral intermediate INT-B is formed via a
cyclic transition state TS-B, which is stabilized by an
intramolecular hydrogen bond between the amine hydrogen
and the carbonyl oxygen, as an example of Bunnett’s built-
in solvation effect. In the case of para substitution, the
stabilization of TS-A heavily relies on solvation. Therefore,
solvents with high SHBB can accelerate Pathway A by
hydrogen bonding strongly with the amine protons11 while
having little effect on Pathway B.
We continued our investigation by considering possible
mechanisms8 for the formation of the regioisomers (Scheme
1). The concept of “built-in solvation,” first proposed by
Bunnett,9 describes the favorable interaction between the
(4) Levin, J. I.; Hopper, D. W.; Torres, N.; Dutia, M. D.; Berger, D. M.;
Wang, X.; Di Grandi, M. J.; Zhang, C.; Dunnick, A. L. Bridged, Bicyclic
Heterocyclic Or Spiro Bicyclic Heterocyclic Derivatives Of Pyrazolo[1,
5-A]Pyrimidines, Methods For Preparation And Uses Thereof. WO 2009/
108838, September 3, 2009.
(8) For a mechanism discussion of the classical SNAr reaction, see:
Carey, F. A.; Sundberg, R. J. AdVanced Organic Chemistry Part A: Structure
and Mechanism 4th; Kluwer Academic/Plenum Publishers: New York,
Boston, Dordrecht, London, Moscow, 2004; pp 589-593.
(9) Bunnett, J. F.; Morath, R. J. J. Am. Chem. Soc. 1955, 77, 5051–
5055.
(5) For a recent review of SNAr reactions, see: Crampton, M. R.
Nucleophilic Aromatic Substitution. In Organic Reaction Mechanisms,
2005; Knipe, C., Eds.; John Wiley & Sons: West Sussex, UK, 2008; pp
155-165.
(6) Lee, K. H.; McPhee, F.; DeVoss, J. J.; Craik, C. S.; Ortiz de
Montellano, P. R. J. Org. Chem. 1994, 59, 6194–6199.
(10) Bishop, R. R.; Cavell, E. A. S.; Chapman, N. R. J. Chem. Soc.
1952, 437–446.
(7) Details in Supporting Information(Table S1, Table S2).
Org. Lett., Vol. 11, No. 24, 2009
5663

Difluoronitrobenzene (5)16 is expected to possess a favorable
conformation17 for the cyclic transition state, thus favoring
formation of the ortho-isomer. Indeed, the ratio of 9a to 9b
was always lower than that of 7a to 7b, as they followed the
same trend across a variety of solvents. Overall, for substrates
1, 4, and 5, five of the six possible regioisomers can be
selectively synthesized in excellent isolated yields (76-98%)18
under the appropriate conditions.
Scheme 2. Solvent Effect on the Regioselectivity of the SNAr
Reactions of Amine 6 and Difluoroarenes Containing Acyl,
Nitro, or Cyano as Activating Groupsa
With the optimized solvents for either para or ortho isomer
synthesis in hand, we were able to selectively prepare both
regioisomers of aminofluoroacetophenone 3 and aminodif-
luoroacetophenone 11 (Scheme 3). In ionic liquid IL1, the
reaction of amine 2 and polyfluoroacetophenone 1 or 10 gave
predominately the para-isomers 3a or 11a, while in dioxane
the reaction afforded only the ortho-isomer 3b or 11b, all
in good yields.
In summary, we have demonstrated that SHBB plays an
important role in controlling the regiochemistry of SNAr
reactions of activated polyfluoroarenes and secondary amines
through its effect on amine hydrogen bonding in the transition
state. A regioselective amination of activated polyfluoroare-
nes has been developed, and efforts are ongoing to expand
this methodology to other substrates and nucleophiles.
This optimal solvent for para-substitution, HMPA, is not
environmentally friendly and requires careful handling for
operator safety. While most common solvents are less
hydrogen-bond basic than HMPA, ionic liquids12,13 repre-
sented intriguing possible alternatives to the phosphoramide.
For example, commercially available ethyl-3-methylimida-
zolium dimethyl phosphate has been reported14a to have
comparable SHBB to HMPA and was used to replace the
toxic solvent. In further studies, we ran the SNAr reactions
(Scheme 2) between a model compound N-Boc-piperazine
(6) and three activated 2,4-difluoroarenes (1, 4, 5) to gain
additional insight into the reaction mechanism.
Scheme 3. Regioselective Amination of
Polyfluoroacetophenonesa
Consistent with the earlier studies, 2,4-difluoroacetophenone
(1) provided the para-substituted product 7a in good correlation
with the SHBBs of dioxane, acetonitrile, and HMPA. The
reaction in the ionic liquid IL1 gave a mixture of 96:4 favoring
7a as expected. In contrast, when the ionic liquid IL2 which
has similar polarity but is much less hydrogen-bond basic than
IL114b was used, the ortho-product 7b15 was dominant. The
electrophile 2,4-difluorobenzonitrile (4) should not be able to
form a cyclic transition state due to its linear geometry (TS-
C). The observed result, that the regioselectivity of the SNAr
for 4 differed much less dramatically in all four polar solvents
regardless of their SHBB, supports our hypothesis. 2,4-
Acknowledgment. We thank Drs. T. Mansour and J.
Ellingboe (Wyeth Research) for their support to this work
and also thank Dr. S. Kwon (Wyeth Research) for her help
in the preparation of the manuscript.
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(11) It has been known that hydrogen bond acceptor solvent can
accelerate SNAr reactions. For a recent example, see: Banjoko, O.;
Babatunde, I. A. Tetrahedron 2005, 61, 8035–8040.
OL902353T
(12) Wasserscheid, P.; Welton, T. Ionic Liquids in Synthesis; Wiley-
VCH Verlag: Stuttgart, Germany, 2002; pp 174-288.
(15) A good yield of 7b has been reported with DMF as solvent: Tucci,
F. C.; Tran, J. A.; Jiang, W.; Pontillo, J.; Marinkovic, D.; White, N. S.;
Arellano, M.; Fleck, B. A.; Wen, J.; Saunders, J.; Foster, A. C.; Chen, C.
Lett. Drug Des. DiscoVery 2006, 3, 311–315.
(13) Recent examples on the use of ionic liquids in SNAr reactions: (a)
D’Anna, F.; Marullo, S.; Noto, R. J. Org. Chem. 2008, 73, 6224–6228. (b)
Newington, I.; Perez-Arlandis, J. M.; Welton, T. Org. Lett. 2007, 9, 5247–
5250. (c) D’Anna, F.; Frenna, V.; Noto, R.; Pace, V.; Spinelli, D. J. Org.
(16) A contrary result in IL2 has been reported: Yadav, J. S.; Reddy,
B. V. S.; Basak, A. K.; Narsaiah, A. V. Tetrahedron Lett. 2003, 44, 2217–
2220.
Chem. 2006, 71, 5144–5150
.
(14) The SHBBs of IL1 and IL2 are reported in Kamlet-Taft parameters
(ꢀ: 1.0(HMPA), 1.0(IL1), 0.2(IL2)) rather than pKHB. (a) Fukaya, Y.;
Hayashi, K.; Wada, M.; Ohno, H. Green Chem. 2008, 10, 44–46. (b) Baker,
S. N.; Baker, G. A.; Bright, F. V. Green Chem. 2002, 4, 165–169.
(17) For 2,4-difluoroacetophenone, the O-trans rotamer is more stable
than the O-cis rotamer. See: Adcock, W.; Rizvi, S. Q. A. Aust. J. Chem.
1973, 26, 2659–2663.
(18) Details in Supporting Information(Table S3).
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Org. Lett., Vol. 11, No. 24, 2009